Abstract
Background
CTB is a currently available oral third-generation cephalosporin that is being developed in combination with the oral prodrug of AVI. In this study, we evaluated the in vitro activity of CTB-AVI against clinical ESBL-like Enterobacterales that were collected from outpatient settings.
Methods
156 ESBL-like Enterobacterales isolates were received from 10 US medical centers that processed cultures from affiliated outpatient centers in 2022. Susceptibility tests for CTB-AVI and standard-of-care antibiotics were performed by CLSI broth microdilution method. Isolates were designated ESBL-like based on cefpodoxime MIC ≥2 mg/L for Proteus mirabilis and ceftriaxone MIC ≥2 mg/L for all other Enterobacterales. Fosfomycin disk diffusion was performed on E. coli isolates only and interpreted according to CLSI M100Ed32 guidance. CTB-susceptible breakpoints currently published by CLSI (≤8 mg/L) and EUCAST (≤1 mg/L) were applied to CTB-AVI for comparison.
Results
Isolates were primarily E. coli (60%) and Klebsiella pneumoniae (16%) and were recovered from patients seen in nursing home/long-term care (38%), urology (21%), and ambulatory care (19%) clinics. Based on CLSI and EUCAST breakpoints, CTB had susceptibility rates of 66% and 32%, respectively. The addition of AVI (fixed concentration of 4 mg/L) to CTB resulted in in vitro potentiation, resulting in 99% (CLSI) and 97% (EUCAST) susceptibility. Susceptibility rates of all isolates against comparator antimicrobials were as follows: cefpodoxime (7%), ceftriaxone (2%), ceftazidime/avibactam (CAZ-AVI) (99.4%), tebipenem (86% at preliminary susceptible breakpoint ≤0.125 mg/L), ertapenem (92.3%), levofloxacin (29%), sulfamethoxazole/trimethoprim (SMX-TMP) (47.4%), and fosfomycin (96%). CTB-AVI had 4-fold lower MIC50/90 values relative to CAZ-AVI (MIC50/90; 0.031/0.25 versus 0.25/1 mg/L). Overall, 100% of levofloxacin and SMX-TMP co-resistant isolates (n=43) were inhibited at CTB-AVI MIC breakpoint concentrations of 8 and 1 mg/L.
Conclusion
These data demonstrate potent in vitro activity of CTB-AVI against ESBL-like Enterobacterales isolated from patients in US nursing homes and outpatient clinics warranting further studies this oral treatment option.
Disclosures
April M. Bobenchik, PhD, Becton Dickinson: Grant/Research Support|BioMerieux: Advisor/Consultant|BioMerieux: Grant/Research Support|BioMerieux: Honoraria|Q-Linea: Grant/Research Support|QuidelOrtho: Grant/Research Support|TechLab: Grant/Research Support Lars Westblade, PhD, Accelerate Diagnostics, Inc: Grant/Research Support|bioMerieux, Inc: Grant/Research Support|Element Materials Technology: Grant/Research Support|Hardy Diagnostics: Grant/Research Support|Roche Molecular Systems, Inc.: Advisor/Consultant|Roche Molecular Systems, Inc.: Grant/Research Support|Selux Diagnostics, Inc.: Grant/Research Support|Shionogi, Inc: Advisor/Consultant|Talis Biomedical: Advisor/Consultant Erik Munson, PhD, Hologic, Incorporated: Advisor/Consultant|Hologic, Incorporated: Honoraria David P. Nicolau, PharmD, CARB-X: Grant/Research Support|Innoviva: Grant/Research Support|Innoviva: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Shionogi: Honoraria|Venatorx: Grant/Research Support Tomefa E. Asempa, PharmD, FDA/CDER: Grant/Research Support|Paratek: Grant/Research Support|Shionogi: Grant/Research Support|Spero: Grant/Research Support|VenatoRx: Grant/Research Support